roche investor day 2012 - hal barron

Creating value through late stage pipeline

Hal Barron, MDHead Global Product Development and Chief Medical Officer

Update on late stage pipeline

ReThink Development

Upcoming newsflow

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Industry shows a broad range of R&D outcomesRoche well placed

Source: EvaluatePharma (May 2012), BCG analysis. "Successful" NMEs are those that achieved or are likely to achieve (based on consensus analyst projections) more than $600 million per year in worldwide peak sales.

UCB

Takeda

Sanofi

Pfizer

Novo Nordisk

Novartis

Merck

Johnson & Johnson

GSK

Lilly

Celgene

BMS

Boehringer Ingelheim

Biogen Idec

Bayer

AZAmgen

Abbott

R&D Spend, 1998-2007 ($ bn)

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NMEs > $600m est. turnover 2002-2011

2011/12: Strong progression of pipeline25 successful late-stage clinical trials

4Positive trials

2 0 1 1

Avastin+pemetrexed

AVAPERL

Avastin+pemetrexed

AVAPERL

Actemra scPhIII JapanActemra scPhIII Japan

TarcevaEURTACTarcevaEURTAC

MetMAbNSCLC

MetMAbNSCLC

Avastin+HerceptinAVEREL

Avastin+HerceptinAVEREL

ZelborafBRIM 3

ZelborafBRIM 3

lebrikizumabMILLY

lebrikizumabMILLY

LucentisRIDE

LucentisRIDE

T-DM1Phase IIT-DM1Phase II

PerjetaCLEOPATRA

PerjetaCLEOPATRA

Avastin OCOCEANS

Avastin OCOCEANS

LucentisRISE

LucentisRISE

ErivedgeERIVANCEErivedge

ERIVANCELucentisHARBORLucentisHARBOR

GA101GAUSSGA101GAUSS

ActemraACT-RayActemraACT-Ray

ActemraBUILDER I/II

ActemraBUILDER I/II

2012

ActemraADACTAActemraADACTA

AvastinTML

AvastinTML

ActemraCHERISHActemraCHERISH

Herceptin scHANNAH

Herceptin scHANNAH

dalcetrapibdal-OUTCOMES

dalcetrapibdal-OUTCOMES

AvastinAURELIAAvastin

AURELIA

MabThera SCSABRINA

MabThera SCSABRINA

AvastinBEATRICE

AvastinBEATRICE

ActemraSUMMACTA

ActemraSUMMACTA

AvastinAVAGLIOAvastin

AVAGLIOT-DM1EMILIAT-DM1EMILIA

aleglitazarAleNephroaleglitazarAleNephro

ActemraBREVACTA

ActemraBREVACTA

New molecular entities in late stageEmerging assets in Neuroscience & Immunology

T-DM1Ph III - HER2+ BC 1L/2LPh II - HER2+ BC EBC

& Gastric

obinutuzumab (GA101)Phase III: –CLL–Diffuse large B-cell lymphoma–Indolent NHL front line–Indolent NHL relapsed

Note: Phase based on FPI5

Oncology Neuroscience Immunology Virology Metabolism

onartuzumab (MetMAb)Ph III– NSCLC Met+ 2L– Gastric cancer HER2-

/Met+Ph II – 1L/2L triple neg. mBC– Met. colorectal 1L – NSCLC, squamous/

non-squamous 1L – Recurrent glioblastoma– Gastric cancer HER2-

bitopertin (Glyt-1)Ph III - Neg. symptoms schiz; Suboptimally controlled schizPh II - Schizophrenia monotherapy

ocrelizumabPhase III: –RR multiple sclerosis–PP multiple sclerosis

lebrikizumabPh III - Asthma

rontalizumabPh II - S. lupus erythematosus

mericitabinePh II - Chronic HepC

danoprevirPh II/III - Chronic HepC

aleglitazarPh III - CV Risk Red post ACS in T2DPh II - Renal function study

PCSK9Ph II - CV disorder ACS

Additional indications for marketed products Highly active lifecycle management

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AvastinFilingOvarian 1L & RelapsedPhase IIIHER2+Adjuvant BCHER2- Adjuvant BCTriple Negative Adj. BCAdjuvant NSCLCHigh risk carcinoidGlioblastoma 1st linemCRC T. Multiple LinesOvarian platinum resistant

Perjeta (pertuzumab)Filing - mBC 1L HER2+ (EU)Phase III - EBC HER2+ BCPhase II - Gastric

ErivedgeFiling - mBCC 1L (EU)

ActemraPhase IIIDMARD IR H2HSubcutaneous formulationEarly RA

Phase IIGiant cell arteritisSystemic sclerosis

XolairPhase III - Chronic Idiopathic Urticaria

LucentisFiling - Diabetes macular edemaPhase I - Sustained delivery

Rituxan / MabTheraFiling - ANCA vasculitis

Rituxan / MabTheraFiling - NHL faster infusionPhase III - SC formulation

HerceptinFiling - SC formulationPhase III - HERA eBC 2yr

TarcevaFiling - NCSLC EGFR mut 1st linePhase III - Adjuvant NCSLC HCC

ZelborafPhase II - Adjuvant MelanomaThyroid Cancer

Oncology Immunology

Note: Phase based on FPI

Roche’s oncology portfolio: Broadest set of technologies for targeted therapies

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Tumour types

TechnologyHER2+ breast

Gastric Breast (Her2-)

Colorectal Lung Ovarian Skin Glio-blastoma

Hema-tological

Drug Conjugates T-DM1 T-DM1 e.g. Anti-CD22

Antibody combinations

Perjeta + Herceptin

Perjeta + Herceptin

MetMab+ Avastin

MetMab + Avastin

EGFL7 + Avastin

MetMab + Avastin

EGFL7 + Avastin

MetMab + Avastin

Glyco-engineered antibodies

GA201 GA201GA101(obinu-

tuzumab)

Immuno-therapies

e.g. Zelboraf +

PDL1

Small molecules PI3K PI3K Zelboraf+

MEKiBcl-2PI3K

Colours indicate projects ongoing or planned in various tumour types

Antibody Drug ConjugatesA new era of targeted medicines

T-DM1Anti-CD22 ADCADC 2

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* *

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*** *

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* *

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Chemotherapy Targeted therapy + chemotherapy

Highly targeted Antibody-Drug Conjugates

e.g. T-DM1e.g. Herceptin, Perjeta, Zelboraf

e.g. Paclitaxel

Evolution of Cancer TherapyTowards a highly targeted approach

*

The next generation of anti-cancer therapyAntibody Drug Conjugates (ADCs)

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Antibody Drug Conjugates combine the specificity of antibodies with the power of

chemotherapy

Antibody targeted to tumor antigen

Very potentchemotherapeutic drug

Linker stable in circulation

Greater therapeutic window

Chemo ADCs

Efficacious dose

Toxic dose

The goal is to create a highly potent therapy with a wider therapeutic

index

1:1

HER2+ (central) LABC or

MBC (N=980)

Prior taxane and trastuzumab

Progression on metastatic tx or within 6 months of adjuvant tx

PDT-DM1

3.6 mg/kg q3w IV

Capecitabine1000 mg/m2

orally bid, days 1–14, q3w

+ Lapatinib

1250 mg/day orally qd

PD

EMILIA StudyT-DM1 in metastatic breast cancer

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Overall survival: interim analysis

Prop

ortio

n su

rviv

ing

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

77.0% 65.4%

47.5%

84.7%

496 469 438 364 296 242 195 155 129 97 74 52 31 17 7 3 2 1 0

495 484 461 390 331 277 220 182 149 123 96 67 46 29 16 5 2 0 0

Cap + Lap

T-DM1

No. at risk:

Median (mos) No. eventsCap + Lap 23.3 129T-DM1 NR 94

Stratified HR=0.621 (95% CI, 0.48, 0.81)P=0.0005

Efficacy stopping boundary P=0.0003 or HR=0.617

Quality of life: Patient reported outcomesTime to symptom progression

Median (mos) NCap + Lap 4.6 445T-DM1 7.1 450

HR=0.80 (95% CI, 0.67, 0.95)

P=0.0121

In collaboration with Immunogen

T-DM1 for early stage HER2-positive breast cancer Aiming to improve over a high bar

• Current standard of care Herceptin+chemo likely to be replaced by Herceptin&pertuzumab+chemo (APHINITY)

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100

80

60

40

20

00 6 12 18 24 30 4836 42

Months from randomisation

Events

458369

4-yearDFS

72.278.6

HR

0.76

95% CI

0.66, 0.87

p value

<0.0001

1-year Herceptin

Observation

Patie

nts

(%)

4 year Disease Free Survival

78.6%

72.2%

Gianni L et al, Lancet Oncology 2011

T-DM1 & pertuzumab*

• Efficacy hurdles high (4 year DFS with Herceptin+chemo ~80%)

• High-risk patients represent high medical need not addressed by current standard of care

Herceptin &pertuzumab*

* Illustrative

• The T-DM1 program aims to demonstrate a benefit over Herceptin and Herceptin & pertuzumab

Early breast cancer strategy A three-pronged approach

Non-pCR adjuvant study• T-DM1 single agent in patients with residual disease

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Neoadjuvant study • T-DM1-based chemotherapy in neoadjuvant setting

Adjuvant study• T-DM1 & pertuzumab vs. Herceptin & pertuzumab in adjuvant setting

Utilizing pCR as surrogate end-point

Setting high bar for clinically meaningful benefit

Targeting indication with high unmet medical need

Screening After 4 cycles

• Currently in phase 1 testing• Early evidence of anti-tumor activity observed

Anti-CD22Antibody Drug Conjugate in hematology

14In collaboration with Seattle Genetics

Example: 79 year old patient with diffuse large B cell lymphoma

Right Inguinal lymph node 2.4 x 3.1 cmPrevious treatments: two Rituxan +chemo regimens(R-CHOP and R-ICE)

Right Inguinal lymph node < 1 cm x 1 cmNo evidence of disease after 4 cycles

Screening After 3 cycles

• Currently in phase 1 testing• Early evidence of anti-tumor activity observed

ADC 2Another lead for treating hematological tumors

15Example: 85 year old patient with mantle cell lymphoma

Right axillary LN 29.0 x 20.1mmPrevious treatments: 6 x R-Benda, rapid PD after 3 cycles of Rituxan

Right axillary LN 0.0 x 0.0mm•81.7% reduction at cycle 3•Continues treatment through cycle 5 today

In collaboration with Seattle Genetics

Antibody Drug Conjugates (ADCs)Extensive pipeline of ADCs for oncology indications

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Early Stage Research

Late StageResearch

Early Development Phase I/II Phase III

RG7600

RG7599

RG7458

RG7598

Anti-CD22

RG7596

Anti-STEAP1

T-DM1ESR

ESR

ESR LSR

RG7636

ESR

ESR

ESR

ESR

ESR

ESR

ESR

ESR

LSR

LSR

Early Dev

ESR

Breast

AML

Melanoma

Colon

Lung

Multiple Myeloma

Ovarian

Prostate

Pancreatic

NHL

Key

As of July 25th, 2012

Diagnostics

Hematological cancersMultiple shots on goal

MabThera/RituxanObinutuzumab (GA 101)Bcl-2Anti-CD22 ADC

Hematological cancersDifferent mechanisms of action

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Bcl-2

2012 2014 2020

GA 101

20182016

Anti-CD22 ADC

MabThera Rituxan*

* Patent expiry in the US: 2018

Potential filing of first indication

Obinutuzumab (GA101)Potential to re-shape biologic hematological market

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today’s standard of care potential future standard of care

2010 2016

MabThera GA101 (CLL11)

2012 2013 2014 20152011

1L Indolent NHL MabThera GA101 (GALLIUM)

Aggressive NHL

2017 2018 2019 2020

CLL

MabThera GA101 (GOYA)

RefractoryIndolent NHL MabThera GA101 (GADOLIN)

In collaboration with Biogen Idec

Filing timelines

Obinutuzumab (GA101) Efficacy target profile

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Indication Efficacy target profile1L DLBCL PFS HR 0.75 vs. rituximab - 3-year PFS rate from 60% to 68%

1L follicular NHL PFS HR 0.74 vs. rituximab – median PFS from 6 8.1 years (35% improvement)

Refractory follicular NHL

PFS HR 0.7 vs. bendamustine – median PFS from 9.3 13.3 months(~43% improvement)

1L CLL PFS HR 0.44 vs. Chlorambucil – median PFS from 12 to 27 months (stage 1)PFS HR 0.74 vs. rituximab – median PFS from 20 to 27 months (stage 2)

Based on in house statistical modelling including available MabThera/Rituxan chemo-combination data in NHL, a 7-8% improvement in ORR is estimated to correspond to a PFS HR of 0.75

First trial to report: 1L in CLL in 2013Recruitment is currently ahead of schedule in all phase III trials

GDC-0199 clinical activity in Phase 1 CLL trial

Week 24Week 12Week 6Cohort 4




Bcl-2 selective inhibitorBcl-2, an important target in hematological cancers

21In collaboration with Abbott

• RG 7601 (GDC-0199) is a Bcl-2 selective, small molecule BH3 mimetic currently in phase I

• Small molecule BH3 mimeticsneutralize pro-survival proteins and promote apoptosis

• Pro-survival proteins, particularly Bcl-2, Bcl-xL, and Mcl-1 are over-expressed in hematopoietic and solid tumors and facilitate chemotherapeutic resistance

Onartuzumab (MetMAb)A broad development programme

Onartuzumab (MetMAb)A new compound that inhibits HGF-mediated activation

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• Monovalent format designed to prevent HGF-mediated stimulation of pathway

• Preclinical activity across multiple tumor models

HGF=Hepatocyte Growth Factor

MetMAb

Met

α α

HGF HGF

Met

No ActivityCell growth, migration, survival

Initiated/planned trials Potential additional indications

Non-small cell lung carcinoma (NSCLC)

Renal cell carcinoma (RCC)

Triple negative metastatic breast cancer

Hepatocellular carcinoma (HCC)

Gastric cancer Prostate cancer

Colorectal cancer (CRC) Ovarian cancer

Glioblastoma multiforme (brain cancer)

Head and neck squamous cell cancer

Rationale for targeting Met• Amplified, mutated, overexpressed or uniquely

activated in various cancers• Overexpression associated with worse prognosis

Cancers where Met may play a role

Note: + = censored value.

Time to progression (months)0 3 6 9 12 15 18

Prob

abili

ty o

f pro

gres

sion

free

0.0

0.2

0.4

0.6

0.8

1.0

Overall survival (months)0 3 6 9 12 15 18 21

Prob

abili

ty o

f sur

viva

l0.0

0.2

0.4

0.6

0.8

1.0

Note: + = censored value.

Progression Free Survival Overall Survival

24Spigel et al. ASCO 2011

Onartuzumab + Tarceva in lung cancer Efficacy analysis in overall population

Placebo +erlotinib

MetMAb +erlotinib

Median (mo) 2.6 2.2HR (95% CI) 1.09 (0.73-1.62)Log-rank p-value 0.69No. of events 56 48

Placebo +erlotinib

MetMAb +erlotinib


Time to progression (months)0 3 6 9 12 15 18

Prob

abili

ty o

f pro

gres

sion

free

0.0

0.2

0.4

0.6

0.8

1.0

Overall survival (months)0 3 6 9 12 15 18 21

Prob

abili

ty o

f sur

viva

l0.0

0.2

0.4

0.6

0.8

1.0

PFS: HR=0.53 OS: HR=0.37

52% patients enrolled were Met-positive

Spigel et al. ASCO 2011

Onartuzumab+Tarceva in Met+ lung cancerNew example of Personalised Healthcare approach

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Placebo +erlotinib

MetMAb +erlotinib


Placebo +erlotinib

MetMAb +erlotinib

Median (mo) 3.8 12.6HR (95% CI) 0.37 (0.19–0.72)Log-rank p-value 0.002No. of events 26 16

Progression Free Survival Overall Survival

Met -

Met +

ITT population

Increasing evidence for the role of Met across multiple solid tumours

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Hazard RatioHR=1

onartuzumab+Tarceva

rilotumumab+chemo

tivantinib

p-value

0.002

0.012

0.01

0.16

na

0.50

0.63

0.22

0.34

Δ OS vs. control (mo)

1.5

8.8

5.4

3.4

-7.2

na

-4.0

2.2

0.4

Source: ASCO 2011, ASCO 2012, Abstracts 4005, 4006

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2nd/3rd line, Phase IINon Small Cell Lung

Metastatic Colorectal 1st line, Phase II

1st line HER2-, Phase III (Met+)

1st and 2nd line, Phase II

2010 2011 2014

2nd/3rd line, Phase III

Triple Negative Breast

Metastatic Gastric

1st line sq. Phase II

1st line non-sq., Phase II

20132012

1st line HER2-, Phase II (all comers)

Glioblastoma 2nd line, Phase II

Indicates pivotal trial

Onartuzumab clinical developmentIn multiple cancer types in parallel

Synergistic combinations

Fighting cancer’s multiple pathways

Suppressing tumour formation with combinationsExamples of targeting multiple pathways

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Phase I Phase II Phase III Launched

RG7594 (Antiangiogenic)+Avastin

- Triple neg. mBC

Onartuzumab+Avastin

- Triple neg. mBC- mCRC- NSCLC, non-squamous 1L- Recurrent glioblastoma

Anti-EGFL7+Avastin

- NSCLC 1L- Met. Colorectal cancer

Perjeta+Herceptin

- Adjuvant HER2-positive BC (APHINITY)

T-DM1+Perjeta

- HER2-positive BC 1L (MARIANNE)- HER2-positive BC EBC

Perjeta +Herceptin

- HER2-positive BC 1L (CLEOPATRA)

Onartuzumab (MetMAb) and AvastinSuppression higher than sum of the parts

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Met:

• Upregulated in hypoxia

• Promotes pro-angiogenic state (e.g. drives VEGF expression)

• Expressed on endothelial cells

NSCLC(NCI-H596 - Met Ex14D, Met 2+)

In hu-HGF-Tg-SCIDs

Met inhibition + anti-VEGF

Anti-VEGF

MetMAb

Control

Avastin and anti- EGFL7Improving anti-angiogenic treatment

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Anti-VEGF Anti-VEGF + Anti-EGFL7

Some endothelial cells die ECM tracks remain More endothelial cells die

Y Y Y Y Y Y Y YY Y Y Y Y Y Y Y

Tumor vasculatureEndothelial

cells

Extracellular Matrix (contains EGFL7)

Y Y Y Y Y Y Y YY Y Y Y Y Y Y Y

anti-VEGF Escape anti-VEGF Escape + anti-EGFL7

Re-growth along old ECM tracksand into new territories

Re-growth may be inhibited along old tracksInefficient growth into new territories

0

500

1000

1500

2000

0 20 40 60 80 100

Controlantibody

anti-VEGF

anti-VEGF + anti-EGFL7

anti-EGFL7

Tum

or V

olum

es (

mm

3 )

Tumor Growth Plot*

Days

*MDA-MB231 (Breast Ca) Xenograft Model

Metabolic diseasesSelected assets in high medical need areas

AleglitazarAnti-PCSK9

Effects of α/γ PPAR activationNuclear receptors that function as transcription factors

3333

↑ Insulin sensitivity

α

Primary γ effect:improve insulin sensitivity

γ↓ apo-CIII

↑ Fatty acid oxidation

↓ VLDL-TG

↑ Fatty acid uptake

Anti-inflammatory

↑ apo AI, HDL

Primary α effect:improve plasma lipid profile

↑ Beta cellfunction

↑ Fatty acid uptake

↑ Adiponectin secretion

Anti-inflammatory

heart, liver, muscle, vasculature

Adipocytes

Muscle

Source: Nicholls S., ACC 2012

* p < 0.05, **p < 0.0001 vs placebo

** ** **

*

50 µg 150 µg300 µg 600 µg 45 mg

Placebo PioglitazoneAleglitazar1

0

-1

-2

-3

-4

TG/H

DL-

C ra

tio

TG=triglycerides, HD=High density lipoprotein, PAV=percent atheroma volume

Glimepiride Pioglitazone p value between treatment groups

Δ(TG/HDL-C) -0.3±0.2 -1.1±0.2 <0.001

ΔPAV 0.73±0.20 -0.16±0.21 0.002

SYNCHRONY study

Absolute change from baseline in TG/HDL-C ratio at Week 16

«Lowering TG/HDL ratio was (...) associated with a beneficial impact of pioglitazone on progression ofcoronary atherosclerosis in diabetic patients»

Source: Nicholls, J Am Coll Cardiol 2011; 57:153–9

Aleglitazar: Effect on TG/HDL-C ratio suggests an effect on coronary atherosclerosis

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PERISCOPE study

Change in TG/HDL-C ratio vs. change in percent atheroma volume (PAV)

There is evidence of beneficial effect of PPAR agonists on CV-related mortality

35* All-cause mortality, non-fatal MI (including silent MI), stroke, major leg amputation (above ankle), ACS, cardiac interventionincluding CABG or PCI and leg revascularization. RRR=relative risk reduction.

Source: Dormandy JA, et al. Lancet 2005; 366:1279–1289.

Even

ts, %

301 events

Secondary endpoint:all-cause mortality, non-fatal MI or stroke

Pioglitazone25

20

15

10

5

0

572 events

HR = 0.90 (95% CI 0.80–1.02)

p = 0.095 514 events

Time from randomization, months0 6 18 24 3612 30 0 6 18 24 3612 30

Time from randomization, months

358 events

16% RRRHR = 0.84

(95% CI 0.72–0.98) p = 0.027

25

20

15

10

5

0

Primary composite endpoint*

Placebo

PROactive Study: effect of pioglitazone on CV endpoints

ALECARDIO Phase III Cardiovascular outcomes study

36

Standard care1 (diabetes and other CV risk factors)

Aleglitazar 150 μg, once daily

Placebo

Randomization up to 8 weeks post-discharge2 ≥ 2.5 years

Known or recently diagnosed T2DM

Hospitalized for ACSN=7’229

Treatment period≥ 2.5 years and ≥ 950 events

Follow-upperiod4 weeks

Randomization up to 12 weeks post-CABG or PCI2Hospital admission

Week 0 8 12

1 Available at: http://clinicaltrials.gov/ct2/show/NCT01042769 (accessed 01.19.11); 2 Roche data on file

Study finished recruitment in May 2012 and is anticipated to report in 2015

EGFR≥45 ml/min

ALENEPHRO Phase II Renal function study

37

Aleglitazar 150 μg

–2 weeks 0 52 weeks

Study population30≤eGFR < 60 ml/min/1.73 m2

Pioglitazone 45 mg

Treatment* period52 weeks

Run-in period 2 weeks

Follow-upperiod8 weeks

Type 2 Diabetes Patients with

stage 3 chronic kidney disease

N=302

Primary endpointChange of eGFRMDRD from

baseline to end of follow-up

* Treatments were given once daily. MDRD=Modification of Diet in Renal Disease1 Available at: http://clinicaltrials.gov/ct2/show/NCT01042769 (accessed 01.19.11); 2 Roche data on file

Primary Objective To assess that renal effects of aleglitazar 150μg are reversible in

patients with moderate renal impairment

Summary: AleNephro met its primary endpoint

• Primary endpointIn patients with moderate renal impairment and type 2 diabetes, the averagedecrease in eGFR reversed within 8 weeks of discontinuing therapy

• Preliminary safetyReview showed side effects as expected, i.e. most frequent side effects wereweight gain and edema

• Detailed results will be presented at an upcoming medical meeting

38

Despite Statins, LDL-C lowering remains a significant unmet need

33m Statintreated

38m Non-Statin treated

Controlled

Uncontrolled

1.4mStatin Intolerant

TreatmentEligible

12.4m: LDL-C

Lowering Unmet Need

Sources: CDC 2006-2008; NHANES 2005-2008

71mHigh LDL-C

39

U.S. population

Carriers of PCSK9 loss-of-function alleles have lower LDL and fewer CV events

LDL and CHD in PCSK9 LOF carriers

Cohen et al., N Engl J Med 2006;354:1264-72

1.2%

9.7%

LaRosa et al., N Engl J Med 2005; 352: 1425-35

LDL level and CV event rate

PCSK9 LOF carriers have reduced mean LDL level and reduced risk of CHD

40

11.8%

6.3%

African-Americans Caucasians

Anti-PCSK-9 mAb (RG 7652)Status

• Patients treated in Phase I (healthy individuals with elevated LDL-C) experienced significant decreases in LDL-C with or without statins

• Pharmacokinetic results suggest there may be a favorable administration schedule

• Current phase II study is investigating different dosing schedules

• Phase II results available in 2013

Target: Best-in-class for the reduction of CV events on top of statins and other SOC with favorable administration schedule

PCSK-9: Proprotein convertase subtilisin/kexin type 941


ReThink development

Upcoming newsflow

ReThink DevelopmentInitiatives to improve productivity in development

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• Personalised Healthcare• More efficient execution• Smart risk-taking• Innovative trial design

• Increase probability of technicalsuccess

• Reduce costs per trial per patient

ReThink Development: Smart risk-taking

44

• Using novel endpoints – Pathological complete response

(pCR)– Minimal residual disease (MRD)

• FDA new guidance supports surrogate endpoints in oncology


ReThink development

Upcoming newsflow

NME submissions and additional indicationsProjects currently in Phase 2 and 3

46Unless stated otherwise, submissions are planned to occur in US and EU indicates submission to Health Authorities has occurred# negative symptoms and sub-optimal control

OncologyImmunologyVirologyCardioMetabolismNeuroscienceOphthalmologyNME

T-DM1 (RG3502)HER2+ advanced mBC

bitopertin(RG1678) schizophrenia#

mericitabine(RG7128) HCV

obinutuzumab (GA101)(RG7159) CLL

onartuzumab (MetMAb)(RG3638) mNSCLC

ocrelizumab (RG1594)PPMS and RMS

danoprevir (RG7227) HCV

2012 2013 2014 2015 2016 onwards

mGluR5 antag (RG7090)Tx resistant depression

lebrikizumab (RG3637) asthma

EGFR MAb (RG7160)solid tumors

anti-factor D Fab (RG7417)geographic atrophy

aleglitazar (RG1439)CV risk reduction in T2D

Status as of June 30, 2012

TarcevaNSCLC adj (US)

AvastinNSCLC adj

Tarceva (US) NSCLC EGFR mutation 1st line

HerceptinHER2+ BC adj 2 year

Avastinglioblastoma 1st line

AvastinHER2+ BC adj

AvastinHER2- BC adj

Actemraearly RA

Xolair (US)chronic idiopathic urticaria

ActemraRA DMARD IR H2H (EU)

AvastinOC 1st line (US)

ActemraSC formulation

MabTherasc form (EU)

Avastinrelapsed OC (US)

TarcevaNSCLC adj (EU)

Actemrasystemic sclerosis

Zelborafpapillary thyroid cancer

Herceptinsc formulation HER2+

LucentisAMD 0.5 mg PRN (US)

Perjeta HER2+ EBC

Perjeta HER2+ mBC 2ndline

Perjeta HER2+ gastric cancer

AvastinOC platinum resist.

AvastinmCRC TML

Actemrapolyarticular JIA

MabTheraANCA assoc vasculitis (EU)

obinutuzumab (GA101) NHL indolent refractory

obinutuzumab (GA101)NHL aggress. DLBCL

NM

EsA

dditi

onal

indi

catio

ns

(exi

stin

g pr

oduc

ts)

MEKi (RG7421)melanoma

T-DM1 (RG3502)HER2+ mBC 1st line

dual PI3 kinase/mTor (RG7422 /GDC 0980) – solid tumours

2012

Data availability / readoutsA rich pipeline with major decision points up-coming

2013

aleglitazarrenal function study (ALENEPHRO)

MEKi (RG 7421)+Zelborafmet. melanoma

rontalizumablupus2

Bcl-2 (RG7601, GDC 0199)CLL and NHL

etrolizumabulcerative collitis

bitopertinacute exacerbation of symptoms

obinutuzumab (GA 101)CLL

EGFR ADCC Mab (RG7160, GA 201)solid tumours

Ph I

Ph II

danoprevir+setrobuvir+mericitabinehepatitis C (ANNAPURNA)

bitopertinschizophrenia sub-optimally controlled

bitopertinschizophrenia negative symptoms

Oncology

NeuroscienceMetabolismVirologyImmunologyOphthalmology

Phase II

Phase III

HerceptineBC HERA 2 years vs. 1 yearPh III

PI3 kinase (RG 7321)Solid tumours

Anti-EGFL7solid tumours

anti-PCSK9metabolic diseases

crenezumabAlzheimer's (ABBY)

mGluR5 antagonisttreatment resistant depression

Anti factor Dgeographic atrophy

mGluR2 antagonisttreatment resistant depression

gantenerumab1

Alzheimer's

1 Potential interim analysis 2 Presentation at ACR in November 2012

TarcevaEGFR+, adj NSCLC

Avastinhigh risk carcinoid

anti-PCSK9metabolic diseases

47

onartuzumab (MetMab)triple negative breast cancer

roche investor day 2012 - hal barron

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